Ruthenium-catalyzed C7 amidation of indoline C-H bonds with sulfonyl azides

Article abstract of DOI:10.1002/chem.201304236

A ruthenium-catalyzed direct C7 amidation of indoline C-H bonds with sulfonyl azides was developed. This procedure allows the synthesis of a variety of 7-amino-substituted indolines, which are useful in pharmaceutical. The good functional tolerances, as well as the mild conditions, are prominent feature of this method.

Full text of DOI:10.1002/chem.201304236

DOI: 10.1002/chem.201304236
Communication
&
CÀH Activation
Ruthenium-Catalyzed C7 Amidation of Indoline CÀH Bonds with
Sulfonyl Azides
Changduo Pan,[a, b] Ablimit Abdukader,[a] Jie Han,[a] Yixiang Cheng,[a] and Chengjian Zhu*[a]
Abstract: A ruthenium-catalyzed direct C7 amidation of
indoline CÀH bonds with sulfonyl azides was developed.
This procedure allows the synthesis of a variety of 7-
amino-substituted indolines, which are useful in pharma-
ceutical. The good functional tolerances, as well as the
mild conditions, are prominent feature of this method.
The formation of CÀN bonds has been widely studied in the
past decades, because CÀN bonds are prevalent in numerous
natural products and biologically active molecules.[1] Copper-
catalyzed Ullmann and Goldberg couplings,[2] as well as palladi-
um-catalyzed Buchwald–Hartwig aminations[3] with haloarenes
have been widely accepted as the most efficient methods to
construct CÀN bonds. The Chan–Lam coupling reaction with
boronic acids is also an efficient method that features mild re-
action conditions.[4] However, prefunctionalization is required
Scheme 1. Pharmaceutical scaffolds including C7-substituted indolines and
their derivatives.
in these reactions. Undoubtedly, the direct amination/amida-
tion of CÀH bonds to form CÀN bonds represents a straightfor-
ward and promising approach, because it obviates the pre-
functionalization of substrates.[5] The rhodium-catalyzed CÀH
amidation by using sulfonyl azides as an amino source along
with gaseous nitrogen as a by-product was first reported by
Chang[6] and other groups.[7] Subsequently, in 2013, Chang,[8]
Sahoo,[9] Jiao,[10] and Ackermann[11] independently reported the
ruthenium(II)-catalyzed amidation of CÀH bonds with sulfonyl
azides.
The indoline scaffold is a ubiquitous structural motif found
in many alkaloid natural products and bioactive molecules.[12]
Many pharmaceutical scaffolds include C7-substituted indo-
lines or their derivatives (Scheme 1).[13] Therefore, the directing-
group-assisted selective CÀH bond functionalization of indo-
lines at the C7 position is synthetically attractive. For example,
the N-acyl group was employed to accomplish the CÀH aryla-
tion of indolines at the C7 position (Scheme 2).[14] Recently,
Oestreich reported the Pd-catalyzed C7 alkenylation of indo-
Scheme 2. CÀH bond functionalizations of indolines at the C7 position.
lines by using urea as a directing group (Scheme 2).[15] Shortly
afterwards, Antonchick described a Rh-catalyzed C7 alkenyla-
tion of indolines (Scheme 2).[16] However, the CÀH functionali-
zation of indolines at the C7 position has only limited reports.
Moreover, the CÀH amidation of indolines at the C7 position
has never been reported, although 7-amino-substituted indo-
lines are particularly useful in pharmaceuticals (Scheme 1).
Herein, we disclose a ruthenium-catalyzed direct C7 amidation
of indoline CÀH bonds with sulfonyl azides.
[a] C. Pan, A. Abdukader, J. Han, Prof. Dr. Y. Cheng, Prof. Dr. C. Zhu
State Key Laboratory of Coordination Chemistry
School of Chemistry and Chemical Engineering
Nanjing University, Nanjing, 210093 (P.R. China)
E-mail: cjzhu@nju.edu.cn
[b] C. Pan
Wenzhou Institute of Industry & Science
Wenzhou 325000 (P.R. China)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201304236.
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Table 1. Selected results of screening the conditions.
Entry
Additive
Solvent
T [8C]
Yield [%][a]
1
2
3
4
5
6
7
8
9
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
AgOAc
THF
80
80
100
110
80
120
120
80
80
80
80
80
0
0
32
16
CH3CN
dioxane
toluene
CH3OH
DMF
HOAc
DCE
DCE
10
trace
trace
75 (0)[c]
76[b](0)[c]
trace
trace
27
10
11
12
KOAc
CsOAc
–
DCE
DCE
DCE
[a] Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), [RuCl2(p-cymene)]2
(5 mol%), AgSbF6 (20 mol%), additive (50 mol%), solvent (1 mL), 24 h, iso-
lated yield. [b] 10 h. [c] No AgSbF6 was used.
Initially, we examined the reaction of N-acetylindoline (1a)
with tosyl azide (2a) in the presence of [RuCl2(p-cymene)]2
(5 mol%), AgSbF6 (20 mol%), and Cu(OAc)2 (50 mol%). The
effect of solvent is vital to this amidation reaction. Among the
solvents screened, 1,2-dichloroethane (DCE) was the best, pro-
viding 3aa in 75% yield. Other solvents such as dioxane gave
only a poor yield of the product (Table 1, entry 3), whereas THF
and CH3CN were totally ineffective (Table 1, entries 1 and 2). In
the absence of an additive, the reaction provided 27% yield
(Table 1, entry 12). Only traces of the product were detected
when KOAc or CsOAc was employed in the reaction (Table 1,
entries 10 and 11). However, AgOAc enhanced the product for-
mation and shortened the reaction time, affording 3aa in 76%
yield (Table 1, entry 9). Further studies showed that no product
was obtained in the absence of [RuCl2(p-cymene)]2 or AgSbF6.
To evaluate the substrate scope of this protocol, the opti-
mized reaction conditions were applied to a range of indolines.
As illustrated in Figure 1, N-acetyl indolines bearing a series of
substitutions at the C2, C3, C4, or C5 positions were compati-
ble in this reaction, giving good yields. Halogen-substituted in-
dolines were tolerable, affording the corresponding halogen-
substituted products in good yields (Figure 1, 3ca–3ea). In
particular, the bromo group was kept intact during the course
of the reaction, which is valuable for further transformations.
Multisubstituted indolines with substitution either at C2 or C3
also provided the products in good yields (Figure 1, 3ia and
3ja). Moreover, N-benzoyl, N-pivaloyl, and N-1-butyryl indolines
were readily amidated under the present conditions (Figure 1,
3ka–3ma).
Figure 1. Ruthenium-catalyzed C7 amidation of indoline CÀH bonds with
tosyl azides. Reaction conditions: 1 (0.2 mmol), 2a (0.3 mmol), [RuCl2(p-
cymene)]2 (5 mol%), AgSbF6 (20 mol%), AgOAc (50 mol%), DCE (1 mL),
808C, 10 h. Isolated yield.
amidation process to provide the product in a good yield
(Figure 2, 3aj). Notably, thiophene-2-sulfonyl azide also worked
well under the standard conditions (Figure 2, 3ak).
An intermolecular competition experiment with isotopically
labeled 1a’’ was proposed. A kinetic isotope effect (KIE) of kH/
kD =1.5 suggested that the Ru-catalyzed CÀH bond cleavage in
the amidation reaction is reversible. Radical inhibitor 2,6-di-
tert-butyl-4-methylphenol (BHT) was added to the standard
procedure. However, it could not inhibit the reaction efficiency.
This result ruled out the possibility of a radical-mediated mech-
anism. Accordingly, a possible mechanistic pathway of this Ru-
catalyzed amidation reaction is proposed in Scheme 3. Initially,
treatment of [Ru(p-cymene)Cl2]2 with AgSbF6 and OAcÀ gener-
ates the active RuII catalyst. Coordination of the carbonyl
oxygen with the active RuII catalyst delivers the metallacycle in-
termediate A.[17] Subsequently, coordination of the azide to A
to form the Ru-species B, followed by migratory insertion of
the sulfonamido moiety with evolution of N2 gas leads to the
intermediate C.[8] Finally, the amidation product 3aa is pro-
duced and the active ruthenium complex is generated by pro-
tonolysis of C.
Next, we further explored the scope of different sulfonyl
azides, and the results are summarized in Figure 2. All the reac-
tions ran smoothly with indoline 1a, giving good yields, and
various functional groups, such as methoxy, fluoro, chloro,
bromo, nitro, and trifluoromethyl groups, were tolerated.
Naphthalene-2-sulfonyl azide also participated readily in the
In conclusion, we have developed a ruthenium-catalyzed
direct C7 amidation of indoline CÀH bonds with sulfonyl
Chem. Eur. J. 2014, 20, 3606 – 3609
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Communication
al-group tolerance as well as the mild conditions are promi-
nent features of this method.
Experimental Section
Representative procedure
Under air, a Schlenk tube was charged with N-acetylindoline
(32.2 mg, 0.2 mmol), tosyl azide (59.1 mg, 0.3 mmol), [RuCl2(p-
cymene)]2 (6.2 mg, 5 mol%), AgSbF6 (6.8 mg, 20 mol%), AgOAc
(16.6 mg, 50 mol%), and DCE (1 mL). The mixture was stirred at
808C for 10 h. After completion of the reaction, the solvent was
evaporated under reduced pressure and the residue was purified
by flash column chromatography on silica gel (PE/EA 2:1) to give
the product 3aa as a white solid (76%).
Acknowledgements
We gratefully acknowledge the National Natural Science Foun-
dation of China (21172106, 21074054, and 21372114), the Na-
tional Basic Research Program of China (2010CB923303), and
the Research Fund for the Doctoral Program of Higher Educa-
tion of China (20120091110010) for their financial support. C.P.
is thankful the support of Natural Science Foundation of China
(21272178).
Keywords: amidation
ruthenium · sulfonyl azides
·
CÀH activation
·
indolines
·
Figure 2. Ruthenium-catalyzed C7 amidation of N-acetyl indoline CÀH bonds
with sulfonyl azides. Reaction conditions: 1a (0.2 mmol), 2 (0.3 mmol),
[RuCl2(p-cymene)]2 (5 mol%), AgSbF6 (20 mol%), AgOAc (50 mol%), DCE
(1 mL), 808C, 10 h. Isolated yield.
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Scheme 3. Proposed mechanism.
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Published online on February 25, 2014
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